Acid labile substances present a problem to the formulator when formulating a pharmaceutical dosage form for oral use. In order to prevent the substances from contact with the acid reacting gastric juice after oral intake, the conventional way to solve this problem is to coat the dosage form with an enteric coating. The coating is a group of substances/polymers with the common feature of being practically insoluble in acid media, while they are soluble in neutral to alkaline media. For substances that are labile in acid media, but have better stability in neutralto alkaline media, it is often advantageous to add alkaline reacting inactive constituents in order to increase the stability of the active compound during manufacture and storage.
A group of comounds exerting these stability properties are substituted benzimidazoles with the geneal formula I ##STR1## wherein A is an optionally substituted heterocyclic group and R.sup.1, R.sup.2, R.sup.3 , and R.sup.4 are the same or different as defined below and R.sup.5 is H or a lower alkyl, or the compound 2-[(2-dimethylaminobenzyl)sulfinyl]-benzimidazole.
The compounds with the general formula I are virtually biologically inactive as such, but degrade/transform to active inhibitors of certain enzyme systems in acid media.
As examples of compounds with the mentioned properties the compounds described in the patents U.S. Pat. No. 4045 563, EP-1-0 005 129 and BE-898 880 and the patent applications EP-85850258,6, EP-A1-0 080 602, EP-0127 736, EP-0 134 400, EP-0 130 729, EP-0 150 586, DE-3415971 GB-2 082 580 and SE-A-8504048-3 may be mentioned. The last application describes 2-(2-disubstituted-aminobenzyl)sulfinyl benzimidazoles, e.g. 2-(2-dimethylaminobenzyl)sulfinyl benzimidazole, also called, NC-1300 and presented by Prof. S. Okabe at the Symposium on Drug Activity held on Oct. 17, 1985 in Nagoya, Japan, and which interacts with the H.sup.+ K.sup.+ -ATPase after acid degradation within the parietal cells. (See for instance B. Wallmark, A. Brandstroom and H. Larson "Evidence for acid-induced transformation of omeprazole into an active inhibitor of H.sup.+ K.sup.+ -ATPase within the partial cell", Biochemica et Biophysica Acta 778, 549-558, 1984). Other compounds with similar properties are further mentioned in the patent U.S. Pat. No. 4 182 766 and the patent applications GB-2 141 429, EP-O 146 370 and GB-2 082 580. A common feature of these compounds are that they are transformed into the biologically active compounds via rapid degradation/transformation in acid media.
The stability profile of some compounds with the general formula I above is exemplifide in the Table 1 below, where the half-life of the degradation/transformation reaction in solution at pH 2 and 7 are given.
TABLE 1 __________________________________________________________________________ Rate of degradation/transformation of compounds with the general structure ##STR2## Half-life (mintues) for the transformation to the active moiety Compound No A R.sup.2 R.sup.3 at pH = 2 at pH = 7 __________________________________________________________________________ ##STR3## 5-COOCH.sub.3 ;6-CH.sub.3 11 150 ##STR4## 5-CH.sub.3 ;H 5.4 1700 ##STR5## 5-CF.sub.3 ;H 1.9 122 ##STR6## 5-CF.sub.3 ;H 2.0 8.8 ##STR7## 5-OCH.sub.3 ;H 3.7 1620 ##STR8## 5-OCH.sub.3 ;H 4.0 3900 ##STR9## 5-C.sub.2 H.sub.5 ;H 33 not determined __________________________________________________________________________
Substituted sulfoxides, such as for instance the substituted benzimidazoles described in EP-1-0005129 are potent inhibitors of gastric acid secretion. The substituted benzimidazoles are susceptible to degradation/transformation in acid reacting and neutral media.
It is an inherent property of these compounds to be activated to the active moiety in the acid environment within the parietal cells. The activated compound interacts with the enzyme in the parietal cells, which mediates the production of hydrochloric acid in the gastric mucosa. All compounds of the class of substituted benzimidazoles, containing a sulfoxide grouping, which interferes with the H.sup.+ K.sup.+ -ATPase in the parietal cells hitherto known are all also degraded in acid media.
A pharmaceutical dosage form of acid labile substances, which prevents the substances from contact with acidic gastric juice, must be enteric coated. Ordinary enteric coatings, however, are made of acidic compounds. If covered with such a conventional enteric coating, the acid labile substance rapidily decomposes by direct or indirect contact with it, with the result that the preparations become badly discoloured and lose in content of the active compound with the passage of time.
In order to enhance the storage stability, the cores which contain the acid labile substance must also contain alkaline reacting constituents. When such an alkaline core is enteric coated with an amount of a conventional enteric coating polymer such as, for example, cellulose acetate phthalate, that permits the dissolution of the coating and the active drug contained in the cores in the proximal part of the small intestine, it also will allow some diffusion of water or gastric juice through the enteric coating into the cores, during the time the dosage form resides in the stomach before it is emptied into the small intestine. The diffused water or gastric juice will dissolve parts of the core in the close proximity of the enteric coating layer and there form an alkaline solution inside the coateddosage form. The alkaline solution will interfere with the enteric coating and eventually dissolve it.
In DE-A1-3 046 559 a way to coat a dosage form is described. First the dosage form is coated with a water insoluble layer containing microcrystalline cellulose and then with a second enteric coating with the aim to achieve a dosage form which releases the active drug in the colon. This method of preparation will not give the desired release of the compounds with the general formula I above in the small intestine.
U.S. Pat. No. 2 540 979 describes an enteric coated oral dosage form, where the enteric coating is combined with a second and/or first coating of a water insoluble "wax" layer. This method of preparation is not applicable on cores containing a compound with the general formula I since direct contact between substances such as cellulose acetate phthalate (CAP) and a compound of formula I causes degradation and discolouration of the compounds of the formula I.
DE-B2-23 36 218 describes a method to produce a dialysis membrane consisting of a mixture of one or more conventional enteric coating polymers and one or more insoluble cellulose derivatives. Such a membrane will not give a proper protection of the acid labile compounds of the formula I in gastric juice.
DE-A1-1 204 363 describes a three-layer coating procedure. The first layer is soluble in gastric but is insoluble in intestinal juice. The second is water soluble regardless of pH and the third layer is an enteric coating. This preparation as well as the preparation described in DE-A1-1 617 615 result in a dosage form which is not dissolved in gastric juice and which only dissolves slowly in intestinal juice. Such preparations cannot be used for the compounds of the formula I, where a rapid release of the drug in the small intestine is needed. DE-A1 12 04 363 describes coating with three layers to achieve release of a drug in the ileum, an aim which is outside the scope of the present invention. GB-A-1 485 676 describes a way to obtain a preparation which effervesces in the small intestine. This is obtained by the enteric coating of a core containing the active drug and an effervescing system such as a combination of carbonate and/or bicarbonate salt and a pharmaceutically acceptable acid. This formulation cannot be adopted for a pharmaceutical dosage form containing a compound of formula I as the presence of an acid in contact with a compound of formula I in the cores would give as a result that the compound of formula I was degraded.
WO No. 85/03436 describes a pharmaceutical preparation, wherein cores containing active drugs mixed with for instance buffering components such as sodium dihydrogenphosphate with the aim of maintaining a constant pH and a constant rate of diffusion, are coated with a first coating which controls as the diffusion. This formulation cannot be adopted for acid labile compounds where a rapid release in the small intestive is wanted. Direct application of an enteric coating onto the cores would also adversely influence the storage stability of such dosage forms containing acid labile compounds.
Outline of the invention
According to the present invention it has been found that the known acid labile compounds with the general formula I above in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same or different and are
______________________________________ (a) hydrogen (b) halogen, e.g. F, Cl, Br, I (c) CN (d) CHO (e) CF.sub.3 (f) ##STR10## (g) OCR.sup.12 (h) CH(OR.sup.13).sub.2 (i) (Z).sub.n BD (j) aryl containing up to 10 carbon atoms (k) aryloxy containing up to 10 carbon atoms, optionally substituted by alkyl containing 1-6 carbon atoms (1) alkylthio containing 1-6 carbon atoms (m) NO.sub.2 (n) alkylsulfinyl containing 1-6 carbon atoms (o) or wherein adjacent groups R.sup.1, R.sup.2, R.sup.3 and R.sup.4 together with the adjacent carbon atoms in the benzimidazole ring form a 5-, 6-, 7-membered monocyclic ring or a 9-, 10- or 11-membered bicyclic ring, which rings may be saturated or unsaturated and may contain 0-3 hetero atoms selected from N and O, and which rings may be optionally substituted with 1-4 substituents selected from alkyl groups with 1-3 carbon atoms, alkylene radicals containing 4-5 carbon atoms giving spiro compounds, or two or four of these substituents together form one or two oxo groups ##STR11## and R.sup.4 together with the adjacent carbon atoms in the benzimidazole ring form two rings they may be condensed with each other, in which formulas R.sup.11 and R.sup.12, which are the same or different, are (a) aryl containing up to 10 carbon atoms (b) alkoxy containing 1-4 carbon atoms (c) alkoxyalkoxy containing 1-3 carbon atoms in each alkoxy part (d) arylalkoxy containing 1-2 carbon atoms in the alkoxy part and up to 10 carbon atoms in the aryl part (e) aryloxy containing up to 10 carbon atoms (f) dialkylamino containing 1-3 carbon atoms in the alkyl parts, or (g) pyrrolidino or piperidino, optionally substituted with alkyl containing 1-3 carbon atoms; R.sup.13 is (a) alkyl containing 1-4 carbon atoms, or (b) alkylene containing 2-3 carbon atoms; Z is ##STR12## n is 0 or 1; B is (a) alkylene containing 1-6 carbon atoms (b) cycloalkylene containing 3-6 carbon atoms (c) alkenylene containing 2-6 carbon atoms (d) cycloalkylene containing 3-6 carbon atoms, or (e) alkynylene containing 2-6 carbon atoms; D is (a) H (b) CN (c) ##STR13## (d) ##STR14## wherein R.sup.9 is (a) alkoxy containing 1-5 carbon atoms, or (b) dialkylamino containing 1-3 carbon atoms in the alkyl parts; m is 0 or 1; r is 0 or 1; Y is (a) O (b) NH (c) NR.sup.10 ; R.sup.10 is (a) H (b) alkyl containing 1-3 carbon atoms (c) arylalkyl containing 1-2 carbon atoms in the alkyl part and up to 10 carbon atoms in the aryl part (d) aryl containing up to 10 carbon atoms; R.sup.5 is H, CH.sub.3 or C.sub.2 H.sub.5 ; A is expecially a pyridyl group in which R.sup.6 and R.sup.8 are the same r different, are ##STR15## (a) H or (b) alkyl containing 1-6 carbon atoms; R.sup.7 is (a) H (b) alkyl containing 1-8 carbon atoms (c) alkoxy containing 1-8 carbon atoms (d) alkenyloxy containing 2-5 carbon atoms (e) alkynyloxy containing 2-5 carbon atoms (f) alkoxyalkoxy containing 1-2 carbon atoms in each alkoxy group (g) aryl containing up to 10 carbon atoms (h) arylalkyl containing 1-6 carbon atoms in the alkyl part and up to 10 carbon atoms in the aryl part (i) aryloxy containing up to 10 carbon atoms, optionally substituted by alkyl containing 1-6 carbon atoms (j) arylalkoxy contiaining 1-6 carbon atoms in the alkoxy part and up to 10 carbon atoms in the aryl part (k) dialkylaminoalkoxy containing 1-2 carbon atoms in the alkyl substituents on the amino nitrogen and 1-4 carbon atoms in the alkoxy group (l) oxacycloalkyl containing one oxygen atom and 3-7 carbon atoms (m) oxacycloalkoxy containing two oxygen atoms and 4-7 carbon atoms (n) oxacycloalkylalkyl containing one oxygen atom and 4-7 carbon atoms (o) oxacycloalkylalkoxy containing two oxygen atoms and 4-6 carbon atoms, or (p) R.sup.6 R.sup.7, or R.sup.7 and R.sup.8 together with the adjacent carbon atoms in the pyridine ring form a ring wherein the part constituted by R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8, is CHCHCHCH O(CH.sub.2).sub.p S(CH.sub.2).sub.v CH.sub.2 (CH.sub.2).sub.p OCHCH NHCHCH ##STR16## ______________________________________
wherein p is 2, 3 or 4, v is 2 or 3 and the O and N atoms always are attached to position 4 in the pyridine ring; provided that not more than one of R.sup.6, R.sup.7 and R.sup.8 is hydrogen can be formulated into an enteric coated dosage form.
The object of the present invention is thus an enteric coated dosage form of acid labile compounds with the general formula I defined above except the compound omeprazole, 5-methoxy-2-(4-methoxy-3,5dimethyl-2-pyridinyl methyl sulfinyl-1H-benzimidazole. Another compound, which may be enteric coated according to the invention is 2-(2-dimethylaminobenzyl)sulfinyl-benzimidazole. The new preparations are resistant to dissolution in acid media, dissolve rapidly in neutral to alkaline media and have a good stability during long-term storage. The new dosage form is characterized in the following way. Cores containing the acid labile compound mixed with alkaline compounds or an alkaline salt of the acid labile compound optionally mixed with an alkaline compound are coated with two or more layers, whereby the first layer/layers is/are soluble in water or rapidly disintegrating in water and consist(s) of non-acidic, otherwise inert pharmaceutically acceptable substances. This/these first layer/layers separates/separate the alkaline core material from the outer layer, which is an enteric coating. The final, enteric coated dosage form is treated in a suitable way to reduce the water content to a very low level in order to obtain a good stability of the dosage form during long-term storage.
As examples of compounds especially suitable for the pharmaceutical dosage form according to the invention the compounds listed in Table 1 can be mentioned.
The half-life of degradation of the compounds 1-6 in Table 1 in water solution at pH-values less than four is in most cases shorter than ten minutes. Also at neutral pH-values the degradation reaction proceeds rapidly, e.g. at pH=7 the half-life of degradation is between 10 minutes and 65 hours while at higher pH-values the stability in solution for most compounds is much better. The stability profile is similar in solid phase. The degradation is catalyzed by acid reacting substances. The acid labile compounds are stabilized in mixtures with alkaline reacting substances.
From what is said about the stability properties of the acid labile compounds listed above it is obvious that an oral dosage form of the said compounds must be protected from contact with the acid reacting gastric juice in order to reach the small intestine without degradation.